Introductory Lecture.pdf

ELBM 2301 FUNCTIONAL GENOMICS APPLIED TO BIOMEDICAL SCIENCE MD YEAR 2 Assoc Prof Sabrina D DYALL Department of Biosciences and Ocean Studies Faculty of Science University of Mauritius INTRODUCTION TO MODULE ELBM 2301 F...

ELBM 2301 FUNCTIONAL GENOMICS APPLIED TO BIOMEDICAL SCIENCE MD YEAR 2 Assoc Prof Sabrina D DYALL Department of Biosciences and Ocean Studies Faculty of Science University of Mauritius INTRODUCTION TO MODULE ELBM 2301 Functional genomics Categories of human diseases Functional genomics Functional genomics is the study of how genes and intergenic regions of the genome contribute to different biological processes. These genes or regions are studied on a “genome-wide” scale to find candidate genes or regions to analyze in more detail. The goal of functional genomics is to determine how the individual components of a biological system work together to produce a particular phenotype. In functional genomics, we try to use our current knowledge of gene function to develop a model linking genotype to phenotype. Functional Genomics The “omics” in functional genomics 1. Genomics 2. Epigenomics 3. Transcriptomics 4. Proteomics 5. Metabolomics 1. Genomics Genomics is the study of whole genomes of organisms, and incorporates elements from genetics. Genomics uses a combination of recombinant DNA, DNA sequencing methods, and bioinformatics to sequence, assemble, and analyze the structure and function of genomes. It differs from ‘classical genetics’ in that it considers an organism’s full complement of hereditary material, rather than one gene or one gene product at a time. Includes genes, regulatory sequences, and noncoding DNA Genes What is a gene? A gene is all DNA that encodes the primary sequence of some final gene product: either a polypeptide, or an RNA with a structural or catalytic function. Some genes can be expressed in different ways to generate multiple gene products from a single segment of DNA. Genes are not always expressed. Regulatory sequences DNA also contains other segments or sequences that have a purely regulatory function. Regulatory sequences provide signals that may: denote the beginning, or denote the end of genes, or influence the transcription of genes, or function as initiation points for replication or recombination. 2. Epigenomics The genome sequence of an individual is almost entirely the same in every cell. How does a common genome sequence generate a diversity of distinct cell types and responses to the environment? The answer lies partly in chemical modifications to the genome sequence and to proteins that package the genome. Collectively, these modifications are referred to as the epigenome. Epigenetics: the study of chemical modifications at individual loci in the genome Epigenomics: the study of how chemical modifications are established and altered across the entire human genome. Significant features of the epigenome The genome is largely static but the epigenome can vary drastically between cell types; can change over time and in response to the environment; is heritable. 3. Transcriptomics The transcriptome is the set of all transcripts or RNA molecules produced in cells It can also be applied to: the specific subset of transcripts present in a particular cell, or, the total set of transcripts in a given organism As it includes all mRNA transcripts in the cell, the transcriptome also reflects the genes that are being actively expressed at any given time. Why do we need to know the transcriptome of a system? The genome is static. The transcriptome is dynamic: Time-specific Cell-specific Includes ALL transcripts => stable, degraded, spliced, edited, polycistronic etc Much more complex than genome 4. Proteomics Proteomics is the large-scale study of proteomes. A proteome is a set of proteins produced in an organism, system, or biological context. The proteome is not constant: it differs from cell to cell and changes over time. To some degree, the proteome reflects the underlying transcriptome. However, protein activity is also modulated by many factors in addition to the expression level of the relevant gene. 5. Metabolomics Metabolomics is the large-scale study of small molecules, commonly known as metabolites, within cells, biofluids, tissues or organisms. Collectively, these small molecules and their interactions within a biological system are known as the metabolome. Metabolomics is the study of substrates and products of metabolism, which are influenced by both genetic and environmental factors. Metabolomics is a powerful approach because metabolites and their concentrations, unlike other “omics” measures, directly reflect the underlying biochemical activity and state of cells / tissues. Thus metabolomics best represents the molecular phenotype. Functional genomics: a summary Transcriptomics, proteomics and metabolomics describe the transcripts, proteins and metabolites of a biological system, and the integration of these data is expected to provide a complete model of the biological system under study. Disease Historical concepts Early explanations for the occurrence of disease focused on superstition, myths, and religion. Supernatural forces Punishment from God and spirits Example: Ancient Greeks – Pandora’s box Pandora’s box Zeus crammed all the diseases, sorrows, vices, and crimes that afflict humanity into a box and gave it to Mercury. Mercury was very tired from carrying his burden and gave it to Epimetheus for safe keeping. Pandora’s box Epimetheus was the husband of Pandora and both promised not to open the box. However, Pandora wanted desperately to know what was in the box. She waited until Epimetheus was gone. She opened the box, and all of the ills of the world flew out and spread throughout the human world. Categories of human diseases Evolution is a process by which species adapt to their environment. When changes in the DNA improve the fitness of a species, its population reproduces more successfully. When changes are relatively maladaptive, the species may become extinct. At the level of the individual within a species: some mutations improve fitness, most mutations have no effect on fitness, and some are maladaptive. Human Genetic Disease Disease may be defined as maladaptive changes that afflict individuals within a population. Disease is also defined as an abnormal condition in which physiological function is impaired. In this module, a key question is: What is the molecular basis of physiological defects at the levels of DNA, RNA and protein? Diversity of Human Diseases There is tremendous diversity to the nature of diseases because: 1. Mutations affect all parts of the genome => limitless opportunities for maladaptive mutations to occur; 2. There are many mechanisms (next Table) by which mutations can cause disease e.g. Point mutations that change amino acid residues in proteins; Deletions or insertions of DNA, from 1 nt to an entire chromosome; Inversions of the orientation of a DNA fragment. Mechanisms of genetic mutations Diversity of Human Diseases There is tremendous diversity to the nature of diseases because: 3. Most genes function by producing a protein. A disease-causing mutation in a gene results in the failure to produce the gene product with normal function. This has profound consequences on the ability of the cells in which the gene product is normally expressed to function. 4. The interaction of an individual with his/her environment has profound effects on disease phenotype. For example, genetically identical twins may have entirely different phenotypes attributable to environmental influences or to epigenetic effects. Even for highly genetic disorders such as schizophrenia, the concordance rate is never 100%. Four main categories of human disease 1. Single gene (monogenic) disease 2. Complex disease 3. Genomic disease 4. Environmental disease The above categories are interconnected in many ways. The pathophysiology of any disease may be considered multigenic. Two individuals exposed to the same disease-causing stimulus may have entirely different reactions. One may become ill while the other is unaffected. There is a large genetic component to the responses to any disease-causing condition. Four main categories of human disease 1. Monogenic Diseases Single-gene disorders tend to be rare in the general population. Traits segregate in a Mendelian manner. Example of a Monogenic Disease: Sickle-Cell Anemia A single amino acid substitution accounts for the abnormal behaviour of the sickle cell. Single-gene disorder inherited in an autosomal recessive manner. While there are common features (e.g. sickling) of the disease, there is not a single disease phenotype. The pleiotrophic phenotype is caused by the influence of other genes. 2. Complex Diseases In contrast to single-gene disorders, complex disorders are very common in the population. These traits do not segregate in a simple, discrete, Mendelian manner. It is likely that the vast majority of human diseases invoke multiple genes. Examples: Alzheimer’s disease Cardiovascular disease Diabetes Obesity High blood pressure Asthma Four main categories of human disease Complex Diseases Complex disorders are characterised by the following features: 1. Multiple genes are thought to be involved: it is the combination of mutations in multiple genes that defines the disease; 2. Complex diseases involve the combined effect of multiple genes, but they also are caused by both environmental factors and behaviours that elevate the risk of the disease; 3. Complex diseases are non-Mendelian; 4. Susceptibility alleles have a high population frequency: complex diseases are generally more frequent than single-gene disorders; 5. Susceptibility alleles have low penetrance: penetrance is the frequency at which a dominant or homozygous recessive gene produces its characteristic phenotype in a population. 3. Genomic Disorders Large-scale chromosomal abnormalities are extremely common causes of disease in humans. Genomic disorders involve changes in the structure of the genome that cause disease. Some genomic disorders involve large-scale changes in which a chromosome copy is gained (trisomy), or lost (monosomy). Many developmental abnormalities involve a portion of a chromosome. Some involve cytogenetically detectable changes and span million of base pairs. If they are too small to be cytogenetically visible (< 3 Mbp), they are usually referred to as cryptic changes. Genomic Disorders Fecundity and Chromosomal Disorders Chromosomal disorders are an extremely common feature of normal human development. Humans have a very low fecundity relative to most other mammals (50% to 80%). This low fecundity is primarily due to the common occurrence of chromosomal abnormalities. A woman who has already had 1 child has only a 25% chance of achieving a viable pregnancy in any given menstrual cycle; 52% of all women who conceive have an early miscarriage; After in vitro fertilization, pregnancies that are confirmed positive in the first 2 weeks result in miscarriage 30% of the time; >60% of spontaneous abortions that occur at ≤12 weeks gestation are likely due to lethal chromosome abnormalities. 4. Environmental Diseases Environmental diseases are extremely common. These include: Infectious diseases caused by a pathogen; Diseases or other conditions not caused by an infectious agent e.g. malnutrition, poisoning or injury Exposure to high levels of radiation Environmental diseases may have an impact on human evolution. MODULE LEARNING OUTCOMES The major aims of this module are to: 1. review how functional genomics has advanced our understanding of molecular mechanisms associated with common diseases; 2. discuss how genomics and genetics can be used to follow disease inheritance patterns; 3. expose links between epigenomics and disease states; 4. explore the pertinence of personalized medicine.